DESCRIPTION This proposal's long term goal is to increase understanding of mammalian forebrain development. This goal will be advanced by studying the genetic and developmental basis for forebrain defects in a mutant mouse strain. This strain carries a recessive lethal mutation called oto, which in homozygosity produces prenatal loss of the forebrain (aprosencephaly) and lower jaw (agnathia). These craniofacial abnormalities are phenotypically similar to birth defects in humans, which are called by the general name agnathia-holoprosencephaly and which include the effects of fetal alcohol syndrome. Toward identifying the gene responsible for causing such abnormalities in the mouse, this project will map the oto locus to a region of about 1cM on chromosome 1. To trace the defects in affected embryos to their earliest onset, which are hypothesized to arise during neural plate stages, this project will examine affected embryos for aberrations in gene expression both in whole mount and in secretions. Embryological experiments will be performed to test the hypothesis that loss of forebrain is due to loss of signaling capacity by anterior endoderm, using an explant system developed by the applicant. These studies will shed light on processed involved in mammalian forebrain development, and may also provide clues about the causes of craniofacial defects in humans.